Carbene-Controlled Regioselective Functionalization of Linear Alkanes under Silver Catalysis

Control of the regioselectivity in the functionalization of C–H bonds of linear alkanes C2H2n+2 via carbene transfer from diazo compounds is restricted to the use of rhodium-based catalysts, which govern the reaction outcome employing donor–acceptor diazo reagents. At variance with that catalyst-controlled strategy, we present an alternative approach in which employing the appropriate silver complexes containing trispyrazolylborate ligands as catalysts with large differences in their steric and electronic properties, the regioselection is mainly governed by the diazo reagent, which leads to the functionalization of primary or secondary sites of linear alkanes (lacking any activating or directing groups). Donor–acceptor aryl diazoacetates exclusively provide the functionalization of the secondary sites of hexane or pentane, whereas acceptor ethyl diazoacetate leads to an unprecedented level of primary functionalization.

3. Synthesis and identification of products generated by catalytic reactions using monosubstituted diazo compounds. S8 4. Synthesis and identification of products generated by catalytic reactions using aryl diazo compounds. S16

5.
Study of the catalytic reactivity of silver complexes with hexane and monosubstituted diazoacetates. S40 6. General procedure for the study of reactions with aryl diazoacetates. S40 7. Study of the catalytic reactivity of silver complexes with hexane and diethyl diazomalonate. S40 8. NMR spectra and GC traces of reaction crudes. All air and moisture-sensitive manipulations were carried out using standard high vacuum lines and standard Schlenk techniques or inside a glovebox under nitrogen. All reactants were purchased from Sigma-Aldrich or Across and used without further purification. Solvents were dried using a SPS-MBraun system. The compounds 3-(3,5-dimethyl-[1,1'-biphenyl]-4yl)pyrazole, 1 [Tp Br3 Ag]2, 2 Tp( CF3)2,Br) Ag(THF), 3 Me-Tp Me2-biphen Tl 1 and the diazocompounds 4 employed in this work were prepared according to literature procedures. NMR spectra were recorded on Agilent 400 MR or Agilent 500 DD2 spectrometers, 1 H and 13 C NMR shifts are reported relative to tetramethylsilane. FT-IR spectra were collected on a Nicolet IR200 FTIR spectrometer. Elemental analyses were performed on a Perkin-Elmer Series II CHNS/O Analyzer 2400. Crystal structure determination was carried out using a BRUKER D8 FIXED-CHI diffractometer equipped with an Oxford Cryosystems low-temperature device.

Synthesis and identification of products generated by catalytic reactions using monosubstituted diazo compounds.
tert-butyl octanoate 1A. 5 Octanoic acid (0.23 g, 1.64 mmol), tert-butoxypyridine (0.33 g, 2.21 mmol) and boron trifluoride diethyl etherate (0.31 g, 2.21 mmol) in dry toluene (2 mL) were added to a Schlenk tube. The reaction mixture was then allowed to stir at room temperature for 30 min before quenching with anhydrous NaHCO3. Ethyl acetate was then added (30 mL), followed by water (20 mL) and brine (20 mL). The organic layer was separated and dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with 0:4 to 1:4 dichloromethane/hexane as eluent, leading to the desired product as a colorless oil with a yield of 89%. 1 H NMR (400 MHz, CDCl3):  S10 Figure S13: 13 C{ 1 H} NMR spectrum of 1A (100 MHz, CDCl3).

tert-butyl 3-methylheptanoate 1B and tert-butyl 3-ethylhexanoate 1C
Step I. Following a related protocol, 6 the corresponding aldehyde (13.28 mmol) was dissolved in THF (192 mL) with (tert butoxycarbonylmethylene)triphenylphosphorane (5 g, 13.28 mmol), and the reaction mixture was stirred for 16 h. Then, the solution was concentrated under reduced pressure and Et2O was added, the resulting solid being discarded upon filtration. The filtrate was taken to dryness and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc-hexane. The products were obtained in 80% (B) and 82% (C) yields.
Step II. Following a previous protocol, 7 a Schlenk flask was charged with B or C (6 mmol), THF ( Octanoyl chloride (10 mmol), 2,4-dimethylpentan-3-ol (10 mmol) and triethylamine (50 mmol) were added to an ampoule at 60 °C for 4 h. After the reaction was completed, the product was extracted in diethyl ether, filtered over basic alumina and then purified by vacuum distillation S13 obtaining the product 2A as a colorless oil with 75% yield. 8

2,4-dimethylpentan-3-yl 3-methylheptanoate (2B) and 2,4-dimethylpentan-3-yl 3ethylhexanoate (2C).
Products 2B and 2C could not be synthesized independently, so for the quantification of these products, a calibration curve was made with an internal standard (trimethoxybenzene) of the mixture of products derived from the catalysis, the exact ratio being determined by 1 H NMR.

3-ethylhexanoate (3C).
Products 3B and 3C could not be synthesized independently, so for the quantification of these products, a calibration curve was made with an internal standard (trimethoxybenzene) of the mixture of products derived from the catalysis, the exact ratio being determined by 1 H NMR.

Synthesis and identification of products generated by catalytic reactions using aryl diazo compounds.
All products were synthesized following the procedures described in the literature. 4 This consists of three reaction steps as shown in the scheme above.
Step I. In a Schlenk tube potassium tert-butoxide K t BuO (6 mmol, 1.2 equiv.) was suspended in 10 mL of dry dimethylformamide (DMF) at 0 °C under an N2 atmosphere, and 2-(4-Xphenyl)acetate (X = Br, Cl, CF3, H; 5.0 mmol, 1 equiv.) was added at once, followed (10 min) by the corresponding n-bromoalkane (pentane or hexane, 6 mmol, 1.2 equiv.). The reaction was stirred at 0 °C during 5 min and then at room temperature for 1.5 h. Water (10 mL) was added and the solution was extracted with DCM (2 x 30 mL). The combined organic layers were washed with saturated, aqueous solution of NH4Cl (20 mL) and water (3 x 10 mL), dried over MgSO4 and filtered off. Then the filtrate was concentrated obtaining in all cases the products as colorless oils in 90-95% yields. Some of the products were used without further purification prior to the next step, others were purified by flash column chromatography (hexanes/diethyl ether = 65/1).
Step II. The products obtained in step I (7 mmol) were added to a one round-bottom flask with NaOH (35 mmol, 5 equiv.) and H2O (50 mL). The reaction was heated at 120 °C for 18h. Then the solution was treated with Et2O (3 x 30 mL), phases were separated, and the aqueous phase was brought to pH = 2 with HCl. Extraction with diethyl ether (3 x 40mL), followed by treatment with MgSO4 led, upon evaporation of the solvent, to the products as colorless or slightly yellow oils with yields between 40-60%. The products were used without prior purification in the next step.
Step III. The product obtained in the step II (4 mmol, 1 equiv) was placed in a Schlenk tube and dissolved in 20 mL of dry DCM. Under nitrogen, the corresponding alcohol (4.4 mmol, 1.1 equiv.) S18 and DMAP (1.2 mmol, 0.3 equiv.) were added at room temperature. The mixture was then cooled at 0°C, then DCC (4.4 mmol, 1.1 equiv) was slowly added dissolved in DCM (2 mL) and with vigorous stirring. The reaction was left stirring at rt for 16h. Then it was filtered off and washed twice with DCM. The solvent was evaporated and the products were purified by silica gel chromatography (Hexane:Et2O, 95:5). In all cases, colorless oils were obtained with yields within the range 54-95%.    S20 Figure S28: 13                   Silver complexes (0.01 mmol) were placed in a Schlenk flask under nitrogen atmosphere with 50 mL of dry hexane. Then the diazocompound (0.15 mmol) was added. For the cases of 2,4dimethylpentan-3-yl 2-diazoacetate and 2,6-di-tert-butyl-4-methoxyphenyl 2-diazoacetate, the catalyst was dissolved in 30 mL and the diazocompounds were added dissolved in 20 mL. The reactions were protected from light with aluminum foil and allowed to stir at rt for 24 h, before evaluating the result by gas chromatography.

General procedure for reactions with aryl diazoacetates.
The silver complexes (0.01 mmol) were placed under nitrogen, in an ampoule for catalyst 4 and in a round bottom flask for complex 2. In both cases, the corresponding alkane (50 mL) was added. Next, the aryl diazocompound (0.15 mmol) dissolved in 30 mL of the alkane was added.
The reactions were protected from light with aluminum foil. In the case of the reactions with hexane using catalyst 4, these were heated at 70 °C for 3 h and at 45 °C for the same time when pentane was used. For complex 2, the reactions were allowed to stir for 15-30 min at room temperature. Then, the solvent was removed and the crude reaction was studied by 1 H NMR with trimethoxybenzene as internal standard. And by GC with calibration curves.

Study of the catalytic reactivity of silver complexes with hexane and diethyl
diazomalonate.
The silver complexes (0.01 mmol) were placed under nitrogen in an ampoule. Hexane (50 mL) and the diazo reagent (0.15 mmol) were added and the reactions were heated at 70 °C for 24 h.
The solvent was then removed under vaccum and the crude reaction was studied by 1 H NMR with trimethoxybenzene as internal standard.